Sleep related breathing disorders (SRBD), especially obstructive sleep apnea (OSA), represent an important health problem, conferring substantial cognitive/behavioral symptoms and increased risk of motor vehicle accident, hypertension, myocardial infarction, stroke, diabetes and death on at least 3% of the US population. Identifying novel treatments for OSA would be of great public health significance, because fully effective and acceptable OSA treatments are lacking. A critical need remains for NIH supported, mechanistically driven proof-of-concept clinical studies to evaluate novel therapeutic strategies. Despite basic research advances regarding the pathogenesis of OSA, generally effective drug treatments have not been identified. Based on our animal and preliminary human data, we propose to test the innovative hypothesis that cannabimimetic drugs are both effective in reducing sleep apnea severity and disease modifying in protecting against cardiovascular and neurological sequelae of OSA. Project 1 will be a randomized, placebo-controlled parallel groups proof-of-concept clinical trial of dronabinol in patients with OSA. Subjects will be randomized to receive either placebo or dronabinol for a period of 6 weeks. The overarching goal will be to establish the safety, tolerability and therapeutic efficacy of dronabinol in OSA, with co-primary efficacy endpoints including: reduction in apnea/hypopnea index (AHI) and improved subjective and objective daytime alertness at the end of treatment. Secondary endpoints will include improved oxygenation, sleep quality, blood pressure control and time-on-treatments effects. Project 2 will employ anesthetized and chronically instrumented conscious behaving animals to directly test the mechanisms of dronabinol action schematized in figure 1. For example, we will characterize dronabinol's dose-dependent inhibition of afferent vagal reflexes elicited by pharmacological and mechanical stimuli. We will use CB1 and CB2 antagonists to confirm the receptor targets for reduced apnea propensity and we will establish the CNS versus vagal-reflex impact of dronabinol on upper airway muscle activity during sleep. We will test the hypothesis that cannabimimetics lower blood pressure by reducing sympathetic activity. Taken together, these projects will provide critical evidence regarding the potential efficacy and mechanisms of action for cannabimimetic treatment of OSA. By providing a path toward the first viable OSA pharmacotherapeutic, the proposed studies could have a tremendous impact on clinical practice.